Increased serum thrombomodulin level is associated with disease severity and mortality in pediatric sepsis

PLOS ONE, Dec 2019

Background Endothelial dysfunction plays an important role in the pathophysiology of sepsis. As previously reported, the serum thrombomodulin is elevated in diseases associated with endothelial injury. Objective The aim of this study was to investigate the association of serum thrombomodulin level in different pediatric sepsis syndromes and evaluate the relationship with disease severity and mortality. Methods We prospectively collected cases of sepsis treated in a pediatric intensive care unit from June 2012 to July 2015 at Chang Gung Children’s Hospital in Taoyuan, Taiwan. Clinical characteristics and serum thrombomodulin levels were analyzed. Results Increased serum thrombomodulin levels on days 1 and 3 of the diagnosis of sepsis were found in different pediatric sepsis syndromes. Patients with septic shock had significantly increased serum thrombomodulin levels on days 1 and 3 [day 1: median, 6.9 mU/ml (interquartile range (IQR): 5.8–12.8) and day 3: median, 5.8 mU/ml (IQR: 4.6–10.8)] compared to healthy controls [median, 3.4 mU/ml (IQR: 2.3–4.2)] (p = <0.001 and 0.001, respectively) and those with sepsis [day 1: median, 2.9 mU/ml (IQR: 1.8–4.7) and day 3: median, 3 mU/ml (IQR: 1.5–3.5)] and severe sepsis [day 1: median, 3.3 mU/ml (IQR: 1.3–8.6) and day 3: median, 4.4 mU/ml (IQR: 0.5–6)] (p = <0.001 and 0.001, respectively). There was also a significant positive correlation between serum thrombomodulin level on day 1 and day 1 PRISM-II, PELOD, P-MOD and DIC scores. The patients who died had significantly higher serum thrombomodulin levels on days 1 and 3 [day 1: median, 9.9 mU/ml (IQR: 6.2–15.6) and day 3: median, 10.4 mU/ml (IQR: 9.2–11.7)] than the survivors [day 1; median, 4.4 mU/ml (IQR: 2.2–7.5) and day 3: [median, 3.5 mU/ml (IQR: 1.6–5.7)] (p = 0.046 and 0.012, respectively). Conclusion Increased serum thrombomodulin levels were found in different pediatric sepsis syndromes and correlated with disease severity and mortality.

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Increased serum thrombomodulin level is associated with disease severity and mortality in pediatric sepsis

August Increased serum thrombomodulin level is associated with disease severity and mortality in pediatric sepsis Jainn-Jim Lin 0 1 2 Hsiang-Ju Hsiao 1 2 Oi-Wa Chan 1 2 Yu Wang 1 2 Shao-Hsuan Hsia 1 2 Cheng-Hsun Chiu 0 1 0 Molecular Infectious Disease Research Center, Chang Gung Children's Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan, 4 Department of Pediatrics, Chang Gung Memorial Hospital at Keelung, College of Medicine, Chang Gung University , Taoyuan, Taiwan , 5 Department of Pediatrics, Chang Gung Memorial Hospital , Chiayi , Taiwan 1 Editor: Dermot Cox, Royal College of Surgeons in Ireland , IRELAND 2 Division of Pediatric Critical Care and Pediatric Sepsis Study Group, Chang Gung Children's Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan, 2 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University , Taoyuan , Taiwan - Data Availability Statement: All relevant data are within the manuscript. Funding: This research was a part of an infection and immunity sepsis project, and was performed by the Pediatric Sepsis Study Group at Chang Gung Children's Hospital in Taoyuan, Taiwan. The work was supported in part by grants from Chang Gung Memorial Hospital (grant: CMRPG3B0841, CMRPG3B0842 and CMRPG3B0843), Taiwan. The funder had no role in study design, data collection Background lial injury. Objective mortality. Methods Results Endothelial dysfunction plays an important role in the pathophysiology of sepsis. As previously reported, the serum thrombomodulin is elevated in diseases associated with endothe The aim of this study was to investigate the association of serum thrombomodulin level in different pediatric sepsis syndromes and evaluate the relationship with disease severity and and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: DIC, disseminated intravascular coagulation; ELISA, enzyme-linked immunosorbent assay; PELOD, Pediatric Logistic Organ Dysfunction; PICU, pediatric intensive care unit; PMOD, Pediatric-Multiple Organ Dysfunction; PRISM, Pediatric Risk of Mortality. mU/ml (IQR: 0.5±6)] (p = <0.001 and 0.001, respectively). There was also a significant positive correlation between serum thrombomodulin level on day 1 and day 1 PRISM-II, PELOD, P MOD and DIC scores. The patients who died had significantly higher serum thrombomodulin levels on days 1 and 3 [day 1: median, 9.9 mU/ml (IQR: 6.2±15.6) and day 3: median, 10.4 mU/ml (IQR: 9.2±11.7)] than the survivors [day 1; median, 4.4 mU/ml (IQR: 2.2±7.5) and day 3: [median, 3.5 mU/ml (IQR: 1.6±5.7)] (p = 0.046 and 0.012, respectively). Conclusion Introduction Increased serum thrombomodulin levels were found in different pediatric sepsis syndromes and correlated with disease severity and mortality. Treating sepsis is a challenge, and it is one of the leading causes of admissions to pediatric intensive care units. The initial manifestation can often be nonspecific and misleading. Severe sepsis is frequently complicated by disseminated intravascular coagulation (DIC) and multiple organ dysfunction syndromes (MODS). Deterioration from sepsis to septic shock and MODS most often occurs in the first 24 hours [ 1 ]. In our previous study, we found decreased a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS 13) activity is associated with disease severity and outcome in pediatric severe sepsis [ 2 ].Despite an improved understanding of the pathophysiology of sepsis, the overall mortality rate remains unacceptably high [ 3 ]. Endothelial dysfunction plays an important role in the pathophysiology of sepsis. Thrombomodulin, a membrane glycoprotein, is expressed on vascular endothelial cells and is found in the body in a bound form and a soluble or plasmatic form [ 4 ]. It binds to thrombin and acts as an anticoagulant. Once thrombomodulin binds to endothelial thrombin, the thrombinthrombomodulin complex accelerates protein C activation [ 4, 5 ], and soluble thrombomodulin is released from the surface of endothelial cells into the serum by proteolytic degradation [6]. As previously reported, the serum thrombomodulin is elevated in diseases associated with endothelial injury, such as acute respiratory distress syndrome [ 7,8 ], disseminated intravascular coagulation [9], and organ dysfunction induced by sepsis [10±12]. Therefore, thrombomodulin is known to be a biomarker of endothelial injury. Since endothelial dysfunction plays an essential role in the pathogenesis of sepsis, some studies have focused on serum thrombomodulin level as a predictor of the severity of sepsis and mortality in adults [10±12]. However, few pediatric studies have examined the role of serum thrombomodulin as a biomarker to predict the clinical course of different (...truncated)


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Jainn-Jim Lin, Hsiang-Ju Hsiao, Oi-Wa Chan, Yu Wang, Shao-Hsuan Hsia, Cheng-Hsun Chiu. Increased serum thrombomodulin level is associated with disease severity and mortality in pediatric sepsis, PLOS ONE, 2017, Volume 12, Issue 8, DOI: 10.1371/journal.pone.0182324